Heart Failure is the most common reason for admission to hospitals in the United States, especially in the Medicare population. A majority of patients with HF have poor left ventricular function, with 60-70% due to chronic ischemic coronary disease. The remainder of patients experience HF due to a variety of other causes, including idiopathic and viral cardiomyopathies, and are classified as dilated non-ischemic cardiomyopathies. Stem cells (endothelial, mesenchymal, skeletal or from bone marrow), injected directly into the myocardium or delivered to the coronary circulation, can improve cardiac function in chronic ischemic cardiomyopathy or following an acute myocardial infarction. While there is evidence that cell therapy can improve cardiac function, the exact mechanisms through which cell therapy exerts beneficial effects remain unclear. We and others have demonstrated that the cardioprotective effects of endothelial progenitor cells (EPCs) following myocardial infarction are mediated, in part, by multiple cytokines secreted by stem cells, which can favorably enhance myocardial survival. We postulate that an enriched, mixed, stem cell population may offer an advantage over a single cell type. It is also evident from our studies that active interaction between stem cells and the vascular wall during systemic delivery is necessary for efficient grafting to occur. This proposal describes two clinical protocols to use bone marrow-derived cells for the treatment of left ventricular dysfunction. The first will test the hypothesis that expansion of bone marrow cells to yield high levels of endothelial and mesenchymal progenitor cells will produce a greater improvement in cardiac function compared to freshly harvested bone marrow cells. The second will investigate the role of cell therapy in dilated non-ischemic cardiomyopathy and test the hypothesis that adenosine pretreatment will enhance cell homing potentiating the beneficial effects of cell therapy. To foster future research, a Clinical Research Skills Development Core will train new clinical investigators in cardiac cell-therapy. The two clinical protocols will determine the efficacy of different cell preparations and the role of modulating stem cell engraftment in target tissue to restore ventricular function opening the way for feasible, easily applied strategies to capture the healing properties of bone marrow-derived cells.